Streptococcus pneumoniae infections are becoming increasingly difficult to manage due to the inability of susceptible individuals to mount appropriate anti -polysaccharide and, to a lesser degree, -surface protein antibody responses as well as increasing antibiotic resistance. Hence, new prophylactic interventions and understanding of pneumococcal immunopathogenesis are greatly needed. This proposal stems from and focuses on our recent findings that RANTES (regulated on activation, normal T cell expressed and secreted) significantly, yet differentially, enhances mucosal and systemic immunity. We present preliminary data that RANTES mRNA mucosal expression is elevated during the primary inflammatory/adaptive recognition response to pneumococcal carriage, which suggests that RANTES is essential for protective mucosal immunity to S. pneumoniae infections. RANTES, MIP-1alpha, and CCR5 polymorphisms resulting in diminished expression are also associated with increased susceptibility to- and progression of- other mucosal pathogens in man. In this regard, our preliminary results show that RANTES blockade leads to the transition of pneumococcal carriage to lethal pneumonia in a mouse model of carriage, using S. pneumoniae strain EF3030. These findings provide the rationale to support the hypothesis that RANTES is essential for the induction of protective mucosal and systemic adaptive immunity against S. pneumoniae. We have emphasized in vivo approaches using mouse models of pneumococcal -carriage and -pneumonia to test this hypothesis. Aim One will assess the recognition phase host immune response to EF3030 challenge in normal, RANTES- or T cell- blocked mice. Aim Two will characterize the adaptive (activation/effector phase) mucosal and systemic immune responses to the phosphorylcholine determinant of C-polysaccharide (PC) and pneumococcal surface adhesin A (PsaA) during pneumococcal disease in control Ab-treated or RANTES-inhibited mice. Aim Three will ascertain the role of RANTES in protection against carriage and/or pneumonia induced by wild type, mutant surface protein (e.g., psaA-) and rough EF3030 strains. This study will provide important and new information regarding the cellular and molecular mechanisms that RANTES uses to induce protective immunity against pneumococci.